Receptors for serotonin (5-hydroxytryptamine, 5-HT) are an important class of G protein-coupled receptors. Serotonin is thought to play a role in processes related to learning and memory, sleep, thermoregulation, mood, motor activity, pain, sexual and aggressive behaviors, appetite, neurodegenerative regulation, and biological rhythms. As expected, serotonin is linked to pathophysiological conditions such as anxiety, depression, obsessive-compulsive disorders, schizophrenia, suicide, autism, migraine, emesis, alcoholism and neurodegenerative disorders.
The serotonin receptors are currently classified into seven subfamilies (5-HT1 through 5-HT7). See, Hoyer, D., et al., “VII International Union of Pharmacology classification of receptors for 5-hydroxytryptamine”, Pharmacol. Rev., 56, 157-203 (1994). The subfamilies have been further divided into subtypes. For example, the 5-HT2 receptor is currently divided into three subtypes: 5-HT2a, 5-HT2b and 5-HT2c. The three subtypes of 5-HT2 receptors are linked to phospholipase C with the generation of two second messengers, diacylglycerol (which activates protein kinase C) and inositol trisphosphate (which releases intracellular stores of Ca2+). The 5-HT2c receptors have a very high density in the choroid plexus, an epithelial tissue that is the primary site of cerebrospinal fluid production. See, Sanders-Bush, E. and S. E. Mayer, “5-Hydroxytryptamine (Serotonin) Receptor agonists and Antagonists”, Goodman & Gilman's The Pharmacological Basis of Therapeutics, Chapter 11, 9th Ed., McGraw-Hill, New York, N.Y. (1996).
Julius, et al., isolated and characterized the 5-HT2c receptor and later reported that transgenic mice lacking the 5-HT2c receptor exhibit seizures and an eating disorder resulting in increased consumption of food (see, U.S. Pat. Nos. 4,985,352 and 5,698,766, respectively). Consequently, compounds selective for the 5-HT2c receptor may provide useful therapies for the treatment of seizure and eating disorders without the side effects typically associated with nonselectivity of the ligand.
Several compounds have been proposed as 5-HT2c receptor agonists or antagonists for use in the treatment of obesity and other related diseases associated with decreased neurotransmission of serotonin in mammals. See, e.g., EP 863136 (azetidine and pyrrolidine derivatives); EP 657426 (tricyclic pyrrole derivatives); EP 655440 (substituted 1-aminoethyl indoles); EP 572863 (pyrazinoindole derivatives); WO98/030548 (aminoalkylindazole compounds); WO 98/56768 (tricyclic pyrrole and pyrazole derivatives); WO 99/43647 (azetidine and pyrrolidine derivatives); WO 99/58490 (aryl-hydronaphthalenalkanamine derivatives); WO 00/12475 (indoline derivatives); WO 00/12482 (indazole derivatives); WO 00/12502 (pyrroloquinoline derivatives); WO 00/12510 (pyrroloindole, pyridoindole and azepinoindole derivatives); WO 00/28993 (naphthylacetylpiperazine derivatives); WO 00/44737 (aminoalkylbenzofuran derivatives); and WO 00/76984 (2,3-disubstituted pyrazines).
The non-selectivity of ligands for the various 5-HT receptors remains a challenge. It is suspected that the non-selectivity of some ligands contributes to various adverse side effects such as hallucinations and cardiovascular complications. Therefore, there remains a need for selective 5-HT2c receptor ligands.